DE10334187A1 - Substituted 2-aminotetralins for the treatment of depression - Google Patents

Abstract

The invention relates to the use of a compound of general formula (I) and the pharmaceutically acceptable salts, racemates or pure enantiomers thereof for the production of a medicament used to treat depression. The substituents are defined as in the description.

Description

To estimates The WHO sees depression as the second leading cause of disease-related disease by 2020 Disability (Murray, Lancet 349 (1997) 1498). The efficiency current pharmacological treatments is for various reasons, e.g. because of late Onset, side effects or lack of efficacy of the drugs limited. Due to the frequency and duration of this disease and the recurrence tendency, there is a great need on new, innovative antidepressants.

From the US 4,564,628 , of the US 4,885,308 , of the US 4,722,933 and WO 01/38321 discloses substituted 2-aminotetralins. These are substances with a dopaminergic effect, which are known in particular for the treatment of Parkinson's disease.

Especially the rotigotine [(-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] amino] -1-naphthol] has become in clinical trials as an effective, transdermally available antiparkinsonian (Metman, Clinical Neuropharmacol., 24, 2001, 163).

worin gilt:
n ist 1–5;
R2 ist OA; R3 und R4 sind jeweils unabhängig voneinander ausgewählt aus H und OA;
wobei A ausgewählt ist aus H, C1-3 Alkyl oder einer Gruppe

worin R6 und R7 jeweils unabhängig voneinander Alkyl, insbesondere C1-20 Alkyl, oder Aryl, insbesondere optional substituiertes Phenyl, sind;
R5 ein C1-3 Alkyl ist;
R1 eine Gruppe ist, die ausgewählt ist aus Wasserstoff, 3-Pyridyl, 4-Pyridyl, optional substituiertem Phenyl,

worin X ausgewählt ist aus S, O oder NH;
wobei die Verbindung der Formel I als Razemat oder als reines (R)- oder (S)-Enantiomer vorliegen kann,
sowie physiologisch akzeptable Salze dieser Verbindungen zur Herstellung von Arzneimitteln zur Behandlung von Depressionen geeignet sind.It has now surprisingly been found that said substituted 2-aminotetralines of the general formula I

where:
n is 1-5;
R2 is OA; R3 and R4 are each independently selected from H and OA;
wherein A is selected from H, C1-3 alkyl or a group

wherein R6 and R7 are each independently alkyl, especially C1-20 alkyl, or aryl, especially optionally substituted phenyl;
R5 is C1-3 alkyl;
R1 is a group selected from hydrogen, 3-pyridyl, 4-pyridyl, optionally substituted phenyl,

wherein X is selected from S, O or NH;
where the compound of the formula I can be present as a racemate or as a pure (R) or (S) -enantiomer,
and physiologically acceptable salts of these compounds are useful in the preparation of medicaments for the treatment of depression.

ist, in der R6 ein C1-20 Alkyl, insbesondere C1-12 Alkyl, Phenyl oder Methoxyphenyl ist.Particularly suitable compounds for preparing an antidepressant are those in which R2 is a group OA and R3 and R4 are independently H or a group OA, with A particularly preferably a hydrogen atom or a group

in which R 6 is a C 1-20 alkyl, in particular C 1-12 alkyl, phenyl or methoxyphenyl.

In another preferred embodiment of the invention R4 is an H.

In another preferred embodiment of the invention, R3 is H.

In another preferred embodiment of the invention R3 and R4 are both H.

In another preferred embodiment of the invention is n = 1, 2 or 3.

wobei X ausgewählt ist aus S, O und NH und wobei X ganz besonders bevorzugt ein Schwefelatom ist.Preferably, R1 is selected from the group

wherein X is selected from S, O and NH and where X is most preferably a sulfur atom.

All R1 is more preferably 2-thienyl.

In a further preferred embodiment of the invention R5 is a C3 alkyl.

In a particularly preferred embodiment The invention relates to the preparation of the medicament for treatment of depressions the racemate of (+/-) 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] amino] -1-naphthol and most preferably the pure S-enantiomer of this compound (Rotigotine) used.

Under the terms "C1-20 Alkyl "," C1-12 Alkyl "," C1-3 alkyl "are each branched or unbranched alkyl groups with the corresponding number of C atoms Understood. For example, a "C1-20 alkyl" includes all alkyls 1 to 20 carbon atoms. The alkyls can optionally substituted, e.g. with halogen. Preferably lie the Alkyle unsubstituted before.

In Two different, validated animal models were used Compounds of the formula I as an antidepressant on the example of rotigotine demonstrated.

The "forced swim test "is a Animal model in which depressive episodes are triggered by acute stress. Rats are forced to swim in a confined space. After initial self-rescue attempts, in which the animals the hopelessness capture, they lapse into immobility. In a repetition In the experiment the animals remain motionless. In pretreatment with antidepressants, the time of immobility is shortened, the Animals start searching and fleeing again (Porsolt, Biomedicine 30, 1979, 139).

In the "learned helplessness test " Rats exposed to chronic uncontrollable stress. this causes in the animals a deteriorated learning ability. After administration of antidepressants normalizes the ability to learn again (Sherman, Pharmacology Biochemistry & Behavior 16, 1982, 449).

In Both tests surprisingly showed subcutaneously given rotigotine a significant antidepressant effect.

1 shows that rotigotine dose-dependently leads to a marked reduction in immobility in the forced swim test.

2 shows that in the "learned helplessness test", animals treated with rotigotine show a dose-dependent normalized learning behavior (NHC) compared to the control group (HC).

From the preclinical data, the conclusion is that with the antiparkinsonian effect Substances of known substituted 2-aminotetralines of general formula I new effective drugs for the treatment of depression could be provided.

Of the Term "treatment" includes in this Patent application both the therapy of existing depression as also the preventive therapy (prophylaxis) of depression, e.g. from recurrent depressive episodes.

depressive disorders will be for better understanding and for optimal individual therapy in subforms divided, the transitions of the different sub-forms are often fluid. The classification the depression takes place - traditionally - after theirs supposed causes or, more recently, theirs Symptoms (see ICD-10 "International Statistical Classification of Diseases and Related Health Problems "of the WHO).

Under The term "depression" will be used in this Patent application both the various, below traditional Undermodes of depression understood as well as those in ICD-10 below the term "affective Disturbances "subsumed disturbances, associated with depressive episodes, especially depressive ones Episodes, recurrent depressive disorders, depressive phases bipolar affective disorders as well as anxiety disorders, adjustment disorders and organic brain disorders, each with depressive symptoms accompanied. Corresponding disturbances For example, in the ICD-10 classifications (Version 2.0, As of November 2000) F31, F32, F33, F41, F43, F45 and F06.

at The traditional division of depression into causes are common 4 main classes:

I. Endogenous depression

• – unipolare Depressionen („major depression"), bei der nur depressive Phasen auftreten
• – bipolare Depressionen („manisch-depressive Störungen"), bei denen depressive Episoden mit manischen Phasen wechseln.

In endogenous depression, no readily identifiable external causes can be identified as triggers of depression. Triggers are likely disorders of the brain's neurotransmitter system. Typical of endogenous depressions is the phase-like course, whereby the depressive episodes can occur repeatedly. Endogenous depression is usually divided into

• - Unipolar depression ("major depression"), in which only depressive phases occur
• - bipolar depression ("manic-depressive disorder") in which depressive episodes alternate with manic phases.

II. Somatogenic depression

• – organische Depressionen, die auf einer Erkrankung oder Verletzung des Gehirns beruhen. Solche Erkrankungen oder Verletzungen, die häufig mit einem veränderten Hirnstoffwechsel einhergehen, sind z.B. Hirntumore, Morbus Parkinson, Migräne, Epilepsie, Hirnlähmung, Hirnarteriosklerose, Hirntraumen, Hirnhautentzündung, Schlaganfall und Demenzen, wie z.B. die Alzheimersche Erkrankung;
• – symptomatische Depression, die oft als Folge oder Begleiterscheinung einer Krankheit aufritt, die die Hirnfunktion nur indirekt beeinflusst. Dies kann z.B. eine Kreislauferkrankung, Hypothyreose oder eine andere Hormonstörung, Infektionskrankheit, Krebs oder Lebererkrankung sein;
• – pharmakogene Depression, z.B. bei Alkohol-, Medikamenten- oder Drogenmissbrauch.

Cause of this depression are physical-organic disorders. In general, somatogenic depression is divided into

• - organic depression, which is based on a disease or injury to the brain. Such diseases or injuries often associated with altered brain metabolism include brain tumors, Parkinson's disease, migraine, epilepsy, cerebral palsy, cerebral arteriosclerosis, brain trauma, meningitis, stroke and dementias such as Alzheimer's disease;
• - symptomatic depression, which often occurs as a result or concomitant of a disease that affects brain function only indirectly. This may be, for example, a circulatory disease, hypothyroidism or other hormonal disorder, infectious disease, cancer or liver disease;
• - pharmacogenic depression, eg in alcohol, drug or drug abuse.

III. Psychogenic depression

These are often overreactions on one or more traumatic experiences. The subdivision is often in Exhaustion depression, neurotic depression and reactive depression based on current Conflicts or events.

IV. Depression in particular of life

Examples are childbed depression, old age depression, depression in childhood, seasonal depression and pubertal depression.

Compounds of the formulas I, in particular rotigotine, and salts thereof are basically suitable for the preparation of a medicament for the treatment of the various types of depression mentioned above or for Treatment of mood disorders, in particular depressive episodes, recurrent depressive disorders, cyclothymia and depressive phases in bipolar mood disorders, suitable according to the ICD-10.

According to the invention Compounds of the formulas I are preferred for the manufacture of a medicament for Treatment of depressive episodes and severe recurrent depressive disorders used, for example, in endogenous, unipolar depression ("major Depression ") occur.

When Reasons for Endogenous, unipolar depressions are metabolic disorders of the Brain cells, i. Noradrenaline or serotonin deficiency and / or a genetic predisposition considered.

The term "major depression" in this patent application refers to a disorder as described in the American Diagnostic Manual "The Diagnostic and Statistical Manual of Mental Disorders - 4 ^th Edition" (American Psychiatric Association, 1994, "DSM IV").

The Compounds of the formula I, in particular rotigotines, and salts thereof are also particularly suitable for the production of antidepressants for the treatment of depressive episodes in manic-depressive patients. These depressive phases in bipolar disorders are discussed in this patent application subsumed under the term "depression".

Further the compounds of the formulas I are preferred for the preparation a drug used to treat "organic" depression, as described above. For example, organic depression occurs often in Parkinson's disease, or in cerebrovascular Diseases and dementia on.

links of the formulas I are optically active and can be used as racemates or as pure R or S enantiomers are present. Under the term "pure Enantiomer "is understood in this patent application that a substance is preferably at least 90 mol% in the form of the one enantiomer, e.g. the (S) -form, exists while the proportion of the other enantiomer, e.g. the (R) -form, accordingly is low. Used for the production of the medicament according to the invention for example rotigotine ([(-) - 5,6,7,8-tetrahydro-6- (propyl [2- (2-thienyl) ethyl] amino] -1-naphthol] used, the R (+) - enantiomer is preferably in a proportion of <10 mol%, particularly preferably with a fraction of <2 mol%, and very particularly preferably with a molar fraction of <1 % based on the total lototigotine amount in the antidepressant.

links of the formula I can as free bases or in the form of the physiologically acceptable salts, e.g. in the form of rotigotine hydrochloride, in the drug.

"Physiologically acceptable Salts "include non-toxic Addition salts of a base, in particular a compound of the formula I in the form of the free base, with organic or inorganic acids. examples for inorganic acids shut down HCl, HBr, sulfuric acid and phosphoric acid one. Organic acids shut down Acetic acid, propionic acid, Pyruvic acid, Butyric, α-, β- or γ-hydroxybutyric, valeric, hydroxyvaleric, caproic, hydroxycaproic, caprylic, capric, lauric, myristic, palmitic, stearic, glycolic, lactic, D-glucuronic, L-glucuronic, D-galacturonic, glycine, benzoic acid, hydroxy benzoic acid, Gallic acid, salicylic acid, Vanillic acid, coumaric acid, caffeic acid, hippuric acid, orotic acid, L-tartaric acid, D-tartaric acid, D, L-tartaric acid, meso-tartaric acid, fumaric acid, L-malic acid, D-malic acid, D, L-malic acid, oxalic acid, malonic acid, succinic acid, Maleic acid, oxaloacetic acid, glutaric acid, hydroxyglutaric acid, ketoglutaric acid, adipic acid, ketoadipic acid, pimelic acid, glutamic acid, aspartic acid, phthalic acid, propane tricarboxylic acid, citric acid, isocitric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid and trifluoromethanesulfonic one.

to Administration of compounds of formula I are various Application routes available, the specialist as needed, condition and age of the patient, required dosage and desired Select application interval and can adapt.

A preferred mode of administration of compounds of formula I. the transdermal dose. The dosage form can in principle be selected from e.g. Ointment, paste, spray, foil, plaster or an iontophoretic Contraption.

Preferably, compounds of the formula I, for example rotigotine, are applied to the skin of the patient in plaster form, wherein the active ingredient is preferably in a matrix of adhesive polymer, for example a self-adhesive the adhesive polysiloxane. Examples of suitable transdermal formulations can be found in WO 99/49852, WO 02/89777 and WO 02/89778. Such a dosage form makes it possible to set a largely constant plasma level and thus a constant dopaminergic stimulation over the entire application interval (WO 02/89778, Metman, Clinical Neuropharmacol., 24, 2001, 163).

Becomes an antidepressant in the form of a subcutaneous or intramuscular Depot form desired, For example, a compound of formula I may be used as a salt crystal, e.g. as a crystalline hydrochloride, in a hydrophobic, anhydrous Medium are suspended and injected as described in WO 02/15903 or in the form of microcapsules, microparticles or implants based on biodegradable polymers, as for example in WO 02/38646 described, administered.

Other conceivable forms of administration of compounds of the formula I. are transmucosal formulations, e.g. Sublingual sprays, rectal Formulations or aerosols for pulmonary administration.

suitable Dosages of compounds of the formula I are in general between 0.1 and about 50 mg / day, preferably daily doses between 0.2 and 40 mg and especially between 0.4 and 20 mg / day become. In this case, the dosage can be done einschleichend, that is, the Treatment may start with low dosages if necessary which are then increased to the maintenance dose.

the It is clear to a person skilled in the art that the dosing interval depends on of the applied quantity, the type of application and the daily requirement of the patient may vary. So can a transdermal application form for example, once a day, three-day or seven-day Administration be conceived while a subcutaneous or intramuscular Depot injections, for example, in a one-, two- or four-week rhythm can.

links of the formula I can used for monotherapy of depression. In one embodiment of the invention in the antidepressant dosage form in addition to compounds of the formula But I also have other active ingredients.

Examples therefor Other antidepressants that directly or indirectly affect the serotonin or norepinephrine metabolism influence indirectly.

• – selektive Serotonin-Wiederaufnahmehemmer wie Sertralin, Citalopram, Paroxetin oder Fluoxetin
• – gemischte Serotonin-, Noradrenalin-Wiederaufnahmehemmer wie Venlaxafin, Milnacipram, Mirtazapin und trizyklische Antidepressiva wie Amitryptilin und Imipramin
• – selektive Noradrenalin-Wiederaufnahmehemmer wie Reboxetin
• – Monoaminoxidase-Hemmer wie Tranylcypramin oder Clorgylin
• – Alpha2-Rezeptor und/oder Serotoninrezeptor-Modulatoren wie Mirtazapin oder Nefazodon.

examples for this are

• - Selective serotonin reuptake inhibitors such as sertraline, citalopram, paroxetine or fluoxetine
• - mixed serotonin, norepinephrine reuptake inhibitors such as venlaxafine, milnacipram, mirtazapine and tricyclic antidepressants such as amitryptiline and imipramine
• - Selective norepinephrine reuptake inhibitors such as reboxetine
• - monoamine oxidase inhibitors such as tranylcypramine or clorgylin
• Alpha2 receptor and / or serotonin receptor modulators such as mirtazapine or nefazodone.

Other examples for Antidepressants are adenosine antagonists, e.g. ST 1535, sigma opioid receptor ligands, NK antagonists such as GW 597599, saredudant or aprepitant, melatonin agonists or modulators of the hypothalamic-pituitary-adrenal axis.

In dependence The cause and symptoms of depression can be a combination drug as well an additional Antipsychotic, sedative, anxiolytic or migraine medication, or contain an active substance which has one or more effects selected from antidepressant, antipsychotic, sedative, anxiolytic or antimigränoider Effect unfolds.

there can the compound of formula I and the additional antidepressant, antipsychotic, sedative, Anxiolytic or migraine agent in the same pharmaceutical formulation, e.g. a combination tablet, or in different application units, e.g. in the form of two separate tablets. Depending on your needs, both can Active ingredients are administered simultaneously or separately.

In a combination preparation For example, a sequential dose can be achieved by using a Dosage form, e.g. one oral tablet, two different ones Layers with differing release profile for the different having pharmaceutically active ingredients. The skilled person is clear that in the context of the present invention, various dosage forms and application schemes are conceivable, all the subject of the invention are.

Examples for antipsychotics are promethazine, fluphenazine, perphenacin, levomepromazine, thioridazine, Perazine, promazine, chlorprothixene, zuclopenthixol, prothipendyl, Flupentixol, zotepine, benperidol, pipamperone, melperone, haloperidol, Bromperidol, sulpiride, clozapine, pimozide, risperidone, quetiapine, Amisulpride, Olanzapine.

Examples for sedatives are diphenhydramine, doxylamine succinate, nitrazepam, midazolam, lormetazepam, Flunitrazepam, Flurazepam, Oxazepam, Bromazepam, Triazolam, Breadizolam, Temazepam, chloral hydrate, zopiclone, zolpidem, tryptophan, zaleplon.

Examples for anxiolytics are fluspirilen, thioridazine, oxazepam, alprazolam, bromazepam, Lorazepam, prazepam, diazepam, clobazam, medazepam, chlordiazepoxide, Dipotassium chlorazepate, nordazepam, meprobamate, buspirone, kavain, hydroxyzine.

Examples for migraine remedies are almotriptan, zolmitriptan, acetylsalicylic acid, ergotamine, dihydroergotamine, Methysergide, Iprazochrome, Ibuprofen, Sumatriptan, Rizatriptan, Naratriptan, Paracetamol.

EXAMPLES

Embodiment 1: Rotigotine patch

1.8 g Rotigotine (free base) are dissolved in 2.4 g of ethanol and added 0.4 g of Kollidon 90F (dissolved in 1 g of ethanol). This mixture becomes a 74% solution of Silicone Polymers (8.9 g BioPSA 7-4201 + 8.9 g BIO-PSA 7-4301 [Dow Corning]) in heptane. After addition of 2.65 g of petroleum ether will the mix for Stirred for 1 hour at 700 rpm to obtain a homogeneous dispersion. After lamination on polyester was at 50 ° C dried. The patch weight was finally 50 g / cm 2.

Embodiment 2: Rotigotine Degotsuspensionen

• (a) 1411.2 g Miglyol 812 was weighed into a Duran bottle. 14.4 g of Imwitor 312 was added to the Miglyol and subsequently for 30 minutes with stirring at 80 ° C heated. The clear solution was cooled to room temperature and filtered.
• (b) 1188 g of the solution prepared under (a) was transferred to a glass laboratory reactor, 12 g Rotigotine added and for 10 minutes with an Ultraturrax at 10,000 rpm under nitrogen homogenized. The suspension was used while the Ultraturrax was running (2,000 UpM) filled in amber glass bottles.

Claims (15)

Use of a compound of the general formula I in which:

n = 1-5; R2 is = OA; R3 and R4 are each independently selected from H and OA; wherein A is selected from H, C1-3 alkyl or a group,

wherein R6 and R7 are independently alkyl or aryl; R5 is a C1-3 alkyl; R1 is a group selected from hydrogen, 3-pyridyl, 4-pyridyl, optionally substituted phenyl,

wherein X is selected from S, O or NH; wherein the compound of formula I is present as a racemate or as a pure (R) or (S) -enantiomer; and physiologically acceptable salts of these compounds for the manufacture of a medicament for the treatment of depression. Use according to claim 1, wherein R 4 = H. Use according to one of the preceding claims, wherein R3 = N Use according to any one of the preceding claims, wherein A is a hydrogen atom or a group

wherein R6 is C1-12 alkyl, phenyl or methoxyphenyl. Use according to one of the preceding claims, wherein n = 1-3. Use according to any one of the preceding claims, wherein R 1 is selected from the group

wherein X is S, O or NH. Use according to one of the preceding claims, wherein X is a sulfur atom Use according to one of the preceding claims, wherein R5 represents a C3 alkyl. Use according to one of the preceding claims, wherein R1 is 2-thienyl. Use according to one of the preceding claims, wherein the compound 5,6,7,8-tetrahydro-6- (propyl [2- (2-thienyl) ethyl] amino] -1-naphthol is. Use according to claim 9, wherein the compound is the pure S-enantiomer (rotigotine). Use according to one of the preceding claims, wherein depression is a unipolar depression [major depression], a depressive phase of a manic-depressive disorder or organic depression is. Use according to one of the preceding claims, wherein the drug for parenteral, transdermal or mucosal Administration is provided. Use according to one of the preceding claims, wherein The rotigotine administered in a dosage of 0.5-50 mg per day becomes. Combination preparation for the treatment of depression comprising a compound according to any one of claims 1-11 and another active ingredient from the group of antidepressants, antipsychotics, sedatives, Anxiolytics or migraine agents.